The goal of this project is to understand the role of altered protein N-myristoylation as a result of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure. Hepatocellular carcinoma is the third leading cause of cancer death in the world. The mechanisms by which TCDD and related halogenated aromatic hydrocarbons induce non-genotoxic hepatocarcinogenesis are largely unknown, and these compounds still represent an area of health risk in both the environment and workplace. Protein N-myristoylation has been implicated in the early stages of tumorigenesis, and we hypothesize that the observed TCDD-induced transcriptional modulation of specific N-myristoyltransferase (NMT) isozymes results in increased N-myristoylation of a subset of proteins that may be involved in hepatocellular carcinogenesis. The major objectives of this project are to identify and characterize these proteins both in vivo and in vitro and to characterize the NMT isozymes that are transcriptionally regulated by TCDD. 2D electrophoresis, mass spectrometry, immunochemistry and fluorescence techniques will be used to identify and characterize target N-myristoylated proteins. Immunochemical, fluorescence and in vitro enzymatic assays will be used to characterize NMT isozymes in terms of substrate specificity and cellular context in relation to target proteins. The data will provide evidence of potential physiological alterations that may lead to disease states such as liver cancer.